This invention provides a method for producing uniform small doses of finely divided substances and more particularly, the invention relates to a technique employing liquid nitrogen as a dispersing medium for the purpose of packaging fine pharmaceutical powders.
The therapy of lung disease often relies on inhaled medications. Bronchodilators have are widely employed in the treatment of asthma. Inhaled aerosolized antiviral agents are employed in the treatment of infectious diseases. Although most inhaled medications are given for their local effect, there is much recent interest in aerosol delivery of medications for systemic absorption. Inhaled drugs, in the form of very small dry powder particles, may be rapidly and directly absorbed into the blood stream. Thus, for example, proteins and peptides may be self-administered rather than administered by injection.
The list of drugs currently under investigation for inhalation delivery is quite extensive. Aerosolized insulin for diabetes is anticipated to become a major application of inhalation therapy.
Most large organic molecules, including proteins and peptides, are denatured by stomach acid when ingested. Absorption in the peripheral parts of the respiratory system overcomes this problem. Thus, the physician has means to provide the patient with a technique whereby the patient may self-administer large molecule medicaments without injection. The value of inhalation therapy in administering insulin, for example, is obvious.
Prior to the development of dry powder inhalers, most inhalation therapies employed pressurized chlorofluorocarbon propellants to disperse drugs. Environmental concern relating to CFC destruction of the earth""s ozone layer has reduced the utility of this approach.
Dry powder inhalers for pulmonary drug delivery require dose levels that range from 25 micrograms to over 1,000 micrograms. Powder particle mean diameters of between 0.5 and 5.0 microns are required to provide effective deposition within the lung since larger particles tend to deposit in upper airways without any useful absorption to the circulatory system.
It is difficult to provide metered doses within the required tolerances at the 25 to 250 microgram levels. High-speed weighing systems are generally limited to dose sizes of about 5,0000 micrograms or greater and thus require the active pharmaceutical be diluted with an excipient, such as lactose powder, in order to increase the total measured mass. This dilution approach is subject to limitations in mixing uniformity and the aspiration of extraneous matter by the patient.
Another approach for low dose packaging involves dispersing the active powder in a medium that is in a liquid state at room temperature. The packaging substrate is then filled or coated and the liquid evaporated leaving the powder residue on the surface of the substrate. This approach has limitations in view of potential chemical reactions between the pharmaceutical medicament and the dispersing solvent. Government agency approvals are often required for the use of this process because of these potential interaction problems.
Yet another approach for low dose packaging involves the electrostatic precipitation of aerosolized medicament onto the surface of the medicament package. Abrams et al, U.S. Pat. No. 5,699,649, describe a system employing an endless belt which is charged, developed with an aerosolized powder, and the powder image then transferred to the package. The direct electrostatic precipitation of aerosolized powder is disclosed in Pletcher, U.S. Pat. No. 5,669,973. An improvement in this electrostatic precipitation apparatus is described by Pletcher et al, U.S. Pat. No. 5,714,007. These electrostatic deposition techniques require complex control equipment to accurately meter the required dosage into each package. The rate of powder deposition is also limited due to particle transit time effects and limitations in the mass density of the aerosol. Difficulties in re-aerosolizing the particles in the user""s inhaler, because of the large electrostatic forces on the charged particles, may also be significant.
Many problems relate to the delivery of dry powder pharmaceuticals to the patient. Several devices rely on inhalation by the patient to provide the power to aerosolize the powder. Young patients, older patients, or patients with asthma often do not have the capacity to strongly inhale. Other inhalers rely on pressurized gas to disperse or aerosolize a powder. Vaghefi, U. S. Pat. No. 5,875,776, employs a gas cylinder to supply the energy required to rupture a sealed dosing cartridge. He also describes an alternate approach employing spring-loaded plungers to penetrate the airtight cover of dosing cartridges.
The present invention provides a cost-effective method for repeatedly filling unit dose packages with accurate masses of fine powder medicament. In addition, the invention provides a simple direct method for packaging fine powders under high pressures of nitrogen gas for subsequent rapid re-aerosolization in inhalers thus eliminating the requirement for an external aerosolizing power source.
The invention provides a process that uniformly mixes a pre-weighed amount of finely divided substance with a known volume or known weight of liquid nitrogen. A uniform dispersion of the powder in the liquid nitrogen medium is obtained after mixing. Small volumetric measures of liquid may then be drawn from the liquid reservoir and deposited onto the surface of a solid substrate. The liquefied nitrogen evaporates to form nitrogen gas leaving a low mass per unit area of finely divided substance on the surface of the substrate. The substrate may be slit, die-cut or otherwise formed into individual packages for use in dry powder inhalers. Alternately, metered liquid dispersions may be deposited into individual capsules, blister packs, or other forms of packaging pre-forms.
Metering and controlling the filling volume may be carried out using any of a number of well known high-speed filling line systems.
The advantages of employing liquid nitrogen in this application include:
1. Liquid nitrogen is chemically inert both because of its chemical makeup and extremely low temperature.
2. Liquid nitrogen is very low in cost; high volume prices are about twenty cents per pound.
3. Liquid nitrogen has a low viscosity, which is of value in processing and mixing.
4. Liquid nitrogen has a very low dielectric constant, which is useful in stabilizing dispersions.
5. The extremely low temperature of liquid nitrogen allows powders to be comminuted without fear of generating high temperatures, which might change the properties of the active ingredient.
6. At room temperature, liquid nitrogen rapidly evaporates.
7. The nitrogen gas realized from the evaporation of the liquid phase may be employed as an inert package atmosphere in the final product.
8. Because of the inert nature of the liquid, the active pharmaceutical may be stored for long periods of time prior to packaging.
9. Technologies for liquid nitrogen shipping, handling, storing, and carrying out processing operations, such as cryogenic grinding, are well developed.
10. A unit dose package may be sealed while still retaining a small amount of liquid nitrogen. As the package is warmed, the liquid nitrogen evaporates to pressurize the sealed package with an inert gas. The high pressure is valuable for re-aerosolizing the powder in the package when used in an appropriate inhaler.
In one embodiment of the invention, a known small mass of fine powder medicament is introduced into a known mass of liquid nitrogen that is contained in a Dewar cryostat. The mixture is stirred until the medicament powder is well dispersed. A small metered quantity of the dispersion is then introduced into a packaging blister. This operation is repeated to sequentially fill an assembly of blister packs. The liquid nitrogen is allowed to gradually evaporate and the blisters sealed, just as the last of the nitrogen liquid is vaporized, in order to maintain the sealed powder in a nitrogen atmosphere. The unit dose blisters are the labeled, bulk packaged and shipped to be utilized in unit dose respiratory inhalers.
In a further embodiment of the invention, the blister is sealed prior to the complete vaporization of the liquid nitrogen. A high pressure then develops in the package as the liquid nitrogen remaining in the package vaporizes. The user would insert the pressurized pack into his inhaler. During inhalation, the user would actuate a mechanism that ruptures the pack thus ejecting the powder, now completely aerosolized, into the air stream being inhaled.